CORE: Neuropathology, Biomarker & Genetics Core C Core Leader: John Q. Trojanowski; Co-Core Leaders: Alice Chen-Plotkin, Edward B. Lee and Vivianna Van Deerlin Core Summary/Abstract The Neuropathology, Biomarker and Genetics Core C in this NIA U19 ? Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias? at the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM) banks and characterizes postmortem brain tissue collected from clinically assessed Alzheimer's disease (AD) patients as well as Parkinson's disease (PD) patients without and with cognitive impairments (CI) or dementia (PDD) and dementia with Lewy body (DLB) patients followed in Core B and studied in Projects I-IV. It also collects plasma, cerebrospinal fluid (CSF) and DNA from these subjects, performs genotyping, and handles genotyping data. PD, PDD and DLB (referred to as Lewy body disorders or LBD) as well as multiple system atrophy (MSA) are a spectrum of synucleinopathies characterized by alpha- synuclein (aSyn) aggregates in neurons referred to as Lewy bodies (LBs) and Lewy neurites (LNs) in PD/PDD/DLB or as glial cytoplasmic inclusions (GCIs) in oligodendrocytes of MSA. LBs are the most common co-pathology in AD while AD and LBD are the most common aging related neurodegenerative dementias. Recent findings suggest that progression of AD with aSyn pathology (AD+aSyn) and LBD could reflect the cell- to-cell spread of pathological aSyn conformers or strains in the nervous system followed by progressive neurodegeneration and there is evidence that tau and aSyn cross-fibrillize each other. Thus, this U19 focuses on the progression of AD+aSyn and LBD as well as mechanisms of CNS cell-to-cell spread of pathological aSyn. Projects I and II showed that MSA may result from a unique aSyn GCI strain (aSyn-GCI strain) that spreads among oligodendroglial cells and is distinct from those aSyn conformers linked to LBs/LNs in neurons of LBD (aSyn-LB strain). Hence, Core C will work closely with Projects I and II wherein distinct strains of pathological aSyn will be analyzed and their features will subsequently be associated with phenotypic, biomarker and genetic patient data in collaboration with Projects III and IV. Core C supports the U19 Center goals by implementing postmortem diagnostic criteria for AD/LBD patients referred for autopsy from Core B, collecting biosamples from these patients and assessing the utility of antemortem diagnostics including studies of potential genetic and biomarker signatures. Core C works closely with all Cores/Projects to support the Center's mission by improving diagnostic methods, and providing samples of brain tissue, biofluids and DNA to investigators within and beyond the Penn U19 Center.